He was the son of a successful businessman was born in Musumba, Congo. He received his education from an American missionary school and later trained as an accountant. In the 1950s he took over a chain of stores in the Katanga province and became involved in politics, founding the CONAKAT party which ran under a banner of an independent, federal Congo.
In the general elections of 1960, CONAKAT won control of the Katanga provincial legislature. That same year the Congo became an independent republic, and in the resulting strife, Tshombe and CONAKAT declared Katanga's secession from the rest of the Congo.
The Christian, pro-Western Tshombe was elected president of Katanga in August of 1960, and declared that "we are seceding from chaos." Favoring continued ties with Belgium, Tshombe asked the Belgian government to send military officers to recruit and train a Katangese army. The Soviet-allied Congo premier Patrice Lumumba and his successor Cyrille Adoula requested intervention from United Nations forces, which they received.
When Lumumba was turned over to Katangan officials, he was executed.
It took the United Nations two years to force Katanga back under Congolese rule. Testimonies regarding U.N. atrocities against the Katangese are contained in Rebels, Mercenaries, and Dividends by Smith Hempstone, and Who Killed the Congo? by Phillipa Schuyler.
In 1963, U.N. forces succeeded in capturing Katanga, forcing Moise Tshombe into exile in Europe. He returned to the Congo to serve in a new Coalition government, but was dismissed from his position the following year by President Kasavabu. In 1966, soon-to-be dictator Mobutu Sese Seko brought charges of treason against Tshombe, and he again fled the country, this time to Spain.